Immuno-Modulator Metallo-Peptide Reduces Inflammatory State in Obese Zucker Fa/Fa Rats

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Abstract

Metabolic syndrome is a prothrombotic and proinflammatory chronic state. In obesity, the adipose tissue secretes various adipokines that take part in a variety of physiological and pathophysiological processes, including immunity and inflammation. Previous studies using a liver damage model treated with the immune-modulator metallo-peptide (IMMP) showed lessening in the degree of inflammation. Therefore, this study was set up to evaluate the anti-inflammatory effect of IMMP in obese Zucker fa/fa rats. We used Zucker-Lepr fa/fa and Zucker-Lean in this protocol. The groups received IMMP 50 ng/kg by i.p., three times per week for 8 weeks. Blood samples were collected by cardiac puncture and the serum was preserved at -80°C until analysis; the liver was excised and preserved in formaldehyde 4%. Analyses were performed to determine cytokine, insulin, glucose, triglyceride and cholesterol levels in serum, and histological analysis was also performed. IMMP treatment of obese rats resulted in decreased levels of proinflammatory cytokines (leptin, lL-6, IL-1betha, INF-gamma) and a chemokine (MCP-1), and increased levels of anti-inflammatory adipokine (adiponectin). In addition, treatment decreased the damage and hepatic steatosis generated in the tissue of obese rats. The IMMP exerted an anti-inflammatory effect in obese rats and therefore may be an effective and safe therapeutic alternative in the treatment of metabolic syndrome.

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Most cited references 44

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Origin and physiological roles of inflammation.

Ruslan Medzhitov (2008)

Inflammation underlies a wide variety of physiological and pathological processes. Although the pathological aspects of many types of inflammation are well appreciated, their physiological functions are mostly unknown. The classic instigators of inflammation - infection and tissue injury - are at one end of a large range of adverse conditions that induce inflammation, and they trigger the recruitment of leukocytes and plasma proteins to the affected tissue site. Tissue stress or malfunction similarly induces an adaptive response, which is referred to here as para-inflammation. This response relies mainly on tissue-resident macrophages and is intermediate between the basal homeostatic state and a classic inflammatory response. Para-inflammation is probably responsible for the chronic inflammatory conditions that are associated with modern human diseases.

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Jean-Philippe Bastard, Mustapha Maachi, Claire Lagathu … (2006)

It now appears that, in most obese patients, obesity is associated with a low-grade inflammation of white adipose tissue (WAT) resulting from chronic activation of the innate immune system and which can subsequently lead to insulin resistance, impaired glucose tolerance and even diabetes. WAT is the physiological site of energy storage as lipids. In addition, it has been more recently recognized as an active participant in numerous physiological and pathophysiological processes. In obesity, WAT is characterized by an increased production and secretion of a wide range of inflammatory molecules including TNF-alpha and interleukin-6 (IL-6), which may have local effects on WAT physiology but also systemic effects on other organs. Recent data indicate that obese WAT is infiltrated by macrophages, which may be a major source of locally-produced pro-inflammatory cytokines. Interestingly, weight loss is associated with a reduction in the macrophage infiltration of WAT and an improvement of the inflammatory profile of gene expression. Several factors derived not only from adipocytes but also from infiltrated macrophages probably contribute to the pathogenesis of insulin resistance. Most of them are overproduced during obesity, including leptin, TNF-alpha, IL-6 and resistin. Conversely, expression and plasma levels of adiponectin, an insulin-sensitising effector, are down-regulated during obesity. Leptin could modulate TNF-alpha production and macrophage activation. TNF-alpha is overproduced in adipose tissue of several rodent models of obesity and has an important role in the pathogenesis of insulin resistance in these species. However, its actual involvement in glucose metabolism disorders in humans remains controversial. IL-6 production by human adipose tissue increases during obesity. It may induce hepatic CRP synthesis and may promote the onset of cardiovascular complications. Both TNF-alpha and IL-6 can alter insulin sensitivity by triggering different key steps in the insulin signalling pathway. In rodents, resistin can induce insulin resistance, while its implication in the control of insulin sensitivity is still a matter of debate in humans. Adiponectin is highly expressed in WAT, and circulating adiponectin levels are decreased in subjects with obesity-related insulin resistance, type 2 diabetes and coronary heart disease. Adiponectin inhibits liver neoglucogenesis and promotes fatty acid oxidation in skeletal muscle. In addition, adiponectin counteracts the pro-inflammatory effects of TNF-alpha on the arterial wall and probably protects against the development of arteriosclerosis. In obesity, the pro-inflammatory effects of cytokines through intracellular signalling pathways involve the NF-kappaB and JNK systems. Genetic or pharmacological manipulations of these effectors of the inflammatory response have been shown to modulate insulin sensitivity in different animal models. In humans, it has been suggested that the improved glucose tolerance observed in the presence of thiazolidinediones or statins is likely related to their anti-inflammatory properties. Thus, it can be considered that obesity corresponds to a sub-clinical inflammatory condition that promotes the production of pro-inflammatory factors involved in the pathogenesis of insulin resistance.

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Monocyte chemoattractant protein 1 in obesity and insulin resistance.

Peter Sartipy, David Loskutoff (2003)

This study identifies monocyte chemoattractant protein 1 (MCP-1) as an insulin-responsive gene. It also shows that insulin induces substantial expression and secretion of MCP-1 both in vitro in insulin-resistant (IR) 3T3-L1 adipocytes and in vivo in IR obese mice (ob/ob). Thus, MCP-1 resembles other previously described genes (e.g., PAI-1 and SREBP-1c) that remain sensitive to insulin in IR states. The hyperinsulinemia that frequently accompanies obesity and insulin resistance may therefore contribute to the altered expression of these and other genes in insulin target tissues. In vivo studies also demonstrate that MCP-1 is overexpressed in obese mice compared with their lean controls, and that white adipose tissue is a major source of MCP-1. The elevated MCP-1 may alter adipocyte function because addition of MCP-1 to differentiated adipocytes in vitro decreases insulin-stimulated glucose uptake and the expression of several adipogenic genes (LpL, adipsin, GLUT-4, aP2, beta3-adrenergic receptor, and peroxisome proliferator-activated receptor gamma). These results suggest that elevated MCP-1 may induce adipocyte dedifferentiation and contribute to pathologies associated with hyperinsulinemia and obesity, including type II diabetes.

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Author and article information

Journal

Journal ID (nlm-ta): Int J Biomed Sci

Journal ID (iso-abbrev): Int J Biomed Sci

Journal ID (publisher-id): IJBS

Title: International Journal of Biomedical Science : IJBS

Publisher: Master Publishing Group

ISSN (Print): 1550-9702

ISSN (Electronic): 1555-2810

Publication date (Print): September 2014

Volume: 10

Issue: 3

Pages: 172-181

Affiliations

[1 ]Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca 62210, Morelos, México;

[2 ]Instituto Nacional de Pediatría, México city 04530, México

Author notes

Corresponding author: Lourdes Rodríguez-Fragoso, Av. Universidad 1001, Chamilpa, Cuernavaca, Morelos 62210, México. Tel: 52 777 3297089; E-mail: mrodriguezf@ 123456uaem.mx .

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Publisher ID: IJBS-10-172

PMC ID: 4198424

SO-VID: 4de27aad-eb59-4c18-aa9b-da3d2ec89dd8

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.5/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Immuno-Modulator Metallo-Peptide Reduces Inflammatory State in Obese Zucker Fa/Fa Rats

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Karger: Nutrition and Dietetics

Most cited references 44

Origin and physiological roles of inflammation.

Recent advances in the relationship between obesity, inflammation, and insulin resistance.

Monocyte chemoattractant protein 1 in obesity and insulin resistance.

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